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EUROPEAN TRENDS IN THE MANAGEMENT OF ADVANCED/METASTATIC GASTRIC CANCER
The aim of palliative CT is to increase survival and palliate the clinical symptoms of the disease, with as
little toxicity and negative impact on QOL as possible. Available data from randomized clinical trials clearly
[60]
show a statistically significant advantage of palliative CT, compared with best supportive care (BSC) . To
improve the efficacy and to reduce the adverse effects of CT, optimal agents and combinations are currently
being sought.

First line
Historically, doublet regimens using platinum and fluoropyrimidine have been frequently used in palliative
setting. Alternative to platinum/ fluoropyrimidine doublet regimen, taxane-based regimen and irinotecan
[61]
plus 5-FU are suggested . Irinotecan and oxaliplatin have shown better tolerability and equivalent time-to-
progression in comparison to cisplatin, and guidelines suggest that these agents are promising substitutes for
cisplatin in combination with fluoropyrimidines as well as capecitabine for 5-FU within doublet and triplet
regimen [53,62,63] .

A meta-analysis demonstrated that adding anthracycline to platinum and fluoropyrimidine doublet signifi-
[64]
cantly improved survival . Additional docetaxel to 5-FU/CDDP (DCF) is another option to strengthen the
CT but careful use is necessary in the palliative setting, due to low margins to toxicity. The V-325 trial and
FLOT trial showed the advantage of additional therapeutic effects by taxane-based triplet regimen [65,66] . Al-
though DCF in V-325 trial was superior to CF in response rate (RR) (37% vs. 25%), time-to-progression (5.6
vs. 3.7 months) and 2-year survival rate (18% vs. 9%), the absolute benefit in terms of survival was less than
4 weeks and was counterbalanced by a significant high 3-4 adverse events rate. Similarly, FLOT regimen
showed improved response rate (49% vs. 28%), better progression free survival (PFS) (9.0 vs. 7.1 months, P =
0.79) and no significant benefit in median OS (17.3 vs. 14.5 months, P = 0.39). Although there were no differ-
ences in serious adverse events, QOL was worse in FLOT group.

These triplet regimens have not demonstrated convincing benefits in terms of survival, but instead increased
toxicity rates. Therefore, these regimens are not generally accepted in the palliative setting, so far. The clini-
cal question of which subgroups may be suitable for the stronger triplet regimens, for locally advanced or
metastatic disease, is currently under investigation.

Second line and more
ESMO/ESSO/ESTRO Guidelines recommend the use of irinotecan, docetaxel and paclitaxel as second line
therapy, since these agents have shown to improve OS and QOL compared to BSC in patients with a good
[67]
performance status . The European guidelines also stress the fact that both paclitaxel and irinotecan
have been directly compared in a Japanese Phase III trial showing similar efficacy in median OS for 8 to 9
[68]
months . The German AIO phase III study demonstrated superiority of irinotecan compared to BSC in
[69]
terms of improvement in tumor-related symptoms as second line therapy . The COUGAR-02 trial con-
firmed that docetaxel achieved a significant benefit in OS (5.2 vs. 3.6 months, P = 0.01) in patients with a
[70]
performance status of 0-2 after failure of fluoropyrimidine/platinum regimen . In spite of the fact that 21%
of patients treated with docetaxel experienced grade 4 toxicities, significantly less pain and a trend towards
less dysphagia and nausea, were reported. Based on the results of these well conducted randomized trials, a
benefit of irinotecan and docetaxel as second-line treatment was clearly established for patients with good
performance status. These treatment options should be offered with close monitoring of potential adverse ef-
fects.

Palliative radiation therapy
Guidelines mention that hypo-fractionated radiotherapy is an effective and well-tolerated treatment option
[71]
for symptomatic locally advanced or recurrent disease . In non-comparative observational studies, the